Monoformate of androstenediol and process for producing same



Patented Sept. 19, 1939 PATENT OFFICE MONOFORMATE 0F PROCESS FOR PR.

Leopold Ruzicka, Zurich,

and Hans Kaegi, Basel,

to the firm Society of ANDRO STENEDIOL AND ODUCINGI SAME and Albert Wettstein Switzerland, assignors Chemical Industry in Basic, Basel, Switzerland No Drawing.

2 Claims.

In application Serial No. 46,967, filed October 26, 1935, there is described a process for making saturated alcohols of the type androstanediol by reduction of the fundamental oxy-ketones or their derivatives in acid, neutral or alkaline solution.

The present invention relates to the manufacture of unsaturated alcohols or derivatives thereof by reducing compounds of the type of dehydroandrosterone or its derivatives, substituted at the hydroxyl group, in neutral or an alkaline solution. As reducing agents, alkali metals in presence of alcohol, aluminium-alcoholate (aluminium-isopropylate or aluminium-benzylate), or organo-metallic compounds like magnesium-alkyl-halides or catalytically excited hydrogen, come into question. In the last case there is advantageously used a non-noble or noble metal catalyst, for instance nickel, cobalt or platinumoxide, and, asa solvent, in particular an aliphatic alcohol of low molecular weight.

It is surprising that in the process of the inven tion the carbon double bond is not attacked but merely the keto-group present is reduced to a carbinol...

For example, starting from A -trans-dehydroandrosterone [A -3-oxy-aetiocholenone- (17) l of Formula I were obtained A -trans-androstene-diols-(3,17) of Formula II:

Example 1 Into a boiling solution of 1 part of A -transdehydroandrosterone in 15 parts of methanol there are introduced in several portions 1.2 parts of sodium. When the reduction is finished, the

\ may be used.

A -trans-androstene- Application June 15, 1936, Serial In Switzerland June 18, 1935 Example 2 Into a gently boiling solution of 14 parts of trans-dehydroandrosterone in 40 parts of npropyl-alcohol there are introduced, whilst stirring, 23 parts of sodium. When the reaction is complete the mixture is cooled, cautiously new $15 tralized with hydrochloric acid, evaporated in a vacuum and mixed with water to precipitate the diol which has been produced. 7 By washing the matter on the filter with water and crystallizing it from methanol or ethyl-acetate, there .is ob- U tained an individual A -trans-androstene-3,17- diol of melting point 182-183" C. Instead of n-propyl-alcohol, another alcohol, for instance ethyl-alcohol or isopropyl-alcohol,

:25 Example 3 2 parts of A -trans-dehydroandrosterone are dissolved in '150 parts of alcohol, 7.5 parts of a nickel catalyst containing a carrier are added,; -3o and the whole is shaken with hydrogen under an excess pressure of 2 meters water column. After a few hours the hydrogen calculated for 1 molecular proportion has been absorbed, the catalyst is filtered and the alcohol in greater part 35 evaporated. From the residue crystallizes pure 3,17-diol of melting point 183.5-184.5 C. Further quantities of the diol can be recovered from the mother liquor.

Instead of nickel as catalyst there may also berm used other non-noble metals, for instance cobalt, copper or mixtures of these metals- Example 4 there may also be used as parent material esters with other aliphatic carboxylic acids, as well as aromatic or alicyclic carboxylic acids, such as for example formic acid, benzoic acid or hexahydrobenzoic acid. In this manner there are obtained the corresponding mono-esters of androstenediol. Trans-dehydro-androstene-ethers, such as for example the methyl or ethyl ether, can also be converted into mono-ethers of the androstenediol.

Example 5 100 parts of platinum-oxide are reduced by shaking them with hydrogen in absolute alcohol. After addition of 1'74 parts of trans-dehydroandrosterone, the mass is further shaken until 1 molecular proportion of hydrogen has been absorbed. Duly worked up, the unsaturated diol of melting point l83.5184.5 C. is obtained.

Instead of platinum-oxide there may also be used for instance platinum as catalyst.

' Example 6 5'76 milligrams of A -trans-dehydro-androsterone of melting point 148 C. are dissolved in 50 cc. of absolute ether, and to the solution is added in drops a 'Grignard solution made from 0.39 gram of magnesium and 2.24 grams of ethyliodide. The whole is heated for 8 hours on a water bath, allowed to stand at room temperature over night, and then decomposed by means of ice and hydrochloric acid. The ethereal solution is washed with bisulphite, sodium carbonate and water, and then dried and evaporated. The residue is dissolved in methyl-alcohol and as usual is boiled for a short time with an alcoholic solution of semicarbazide-acetate. After standing for 24 hours the whole is filtered. If the solution is sufficiently concentrated, the precipitate consists of a mixture of l'l-ethyl-trans-androstene-diol-(3,1"I) of melting point 199200 C. and the semicarbazone of the trans-dehydro-androsterone; by treating the precipitate with ether the semicarbazone, in consequence of its sparing solubility, may be removed. In the case of a dilute solution, only the semicarbazone is precipitated. In that case the alcoholic solution is concentrated somewhat, and the 17-ethyl-transandrostene-diol-(3,17) is frozen out. The mother liquor contains in each case besides 1'7-ethyltrans -androstene diol- (3,17), 3-trans androstene-diol formed by reduction. For isolating it the mother liquor is poured into water and the liquor is'extracted with ether; the ethereal solution is washed, dried and evaporated. The product is crystallized from a mixture of ethyl-acetate and hexane or is sublimed at 140 C. under a pressure of 0.01 millimeter. There is thus obtained a mixture of isomeric 1'7-cis and -tr'ans-3- trans-androstene-diols, melting at 1'73-l73.5 C.

Example 7 5'76 milligrams of A -trans-dehydro-androsterone of melting point 148 C. are dissolved in 50 cc. of absolute ether, and into the solution is dropped a Grignard solution from 0.39 gram of magnesium and 2.6 grams of n-propyl-iodide. The mixture is heated for 8 hours on a water bath, allowed to stand over night at room temperature and then decomposed. in ice and dilute hydrochloric acid. The ethereal solution is 4 washed with bisulphite, sodium carbonate and water, dried and evaporated. The residue is dissolved in methyl-alcohol and boiled for a short time with an alcoholic solution of semi-carbazideacetate. After standing for 24 hours the separated semicarbazone of the trans-dehydroandrosterone is filtered, and the filtrate is poured into water. This liquor is extracted with ether; the ethereal solution is washed, dried and evaporated. The residue is recrystallized from a mixture of ethyl-acetate and hexane and yields the mixture of isomeric l'I-cis and -trans-3-trans-androstenediols described in Example 6.

What we claim is:

1. A process for the manufacture of the monoformate of androstene-diol of the formula CH: CH: H

consisting in reducing the keto-group of the formate of dehydroandrosterone of the formula CH: CH:

to a carbinol group with hydrogen in presence LEOPOLD RUZICKA. ALBERT WETTSTEIN. HANS KAEGI. 

